Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

  • Cell Rep. 2023 Jun 1;42(6):112583. doi: 10.1016/j.celrep.2023.112583.
Enric Mocholi  1 ,  Laura Russo  2 ,  Keshav Gopal  3 ,  Andrew G Ramstead  4 ,  Sophia M Hochrein  5 ,  Harmjan R Vos  6 ,  Geert Geeven  7 ,  Adeolu O Adegoke  8 ,  Anna Hoekstra  9 ,  Robert M van Es  6 ,  Jose Ramos Pittol  6 ,  Sebastian Vastert  10 ,  Jared Rutter  4 ,  Timothy Radstake  11 ,  Jorg van Loosdregt  10 ,  Celia Berkers  12 ,  Michal Mokry  13 ,  Colin C Anderson  8 ,  Ryan M O'Connell  4 ,  Martin Vaeth  5 ,  John Ussher  3 ,  Boudewijn M T Burgering  6 ,  Paul J Coffer  14
Affiliations
  • 1. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: [email protected].
  • 2. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • 4. Huntsman Cancer Institute and Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Salt Lake City, UT, USA.
  • 5. Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany.
  • 6. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 7. Department of Clinical Genetics, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 8. Department of Surgery, University of Alberta, Edmonton, AB, Canada.
  • 9. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
  • 10. Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 11. Laboratory for Translational Immunology and Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 12. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • 13. Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Cardiovascular Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 14. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 37267106 DOI: 10.1016/j.celrep.2023.112583
Abstract

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying Enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.

Keywords
CP: Metabolism; T cell; citrate; epigenetics; epigenome remodeling; glucose metabolism; glycolysis; histone acetylation; nuclear metabolism; pyruvate; pyruvate dehydrogenase.
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